Substituted thiazolopyrimidines

Abstract

The present invention relates to substituted thiazolopyrimidine compounds of general formula I as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyperproliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

The invention claimed is: 
     
       1. A compound of general formula I: 
       
         
           
           
               
               
           
         
         in which: 
         A represents a group selected from: 
       
       
         
           
           
               
               
           
         
         
           wherein * indicates the point of attachment of said groups with the rest of the molecule; 
         
         R 1a , R 1b , R 1c , R 1d  are the same or different and are independently selected from R 1 ; 
         R 1  represents a hydrogen atom or a halogen atom or a hydroxy-, cyano-, C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, C 3 -C 6 -cycloalkyl-, C 4 -C 8 -cycloalkenyl-, C 3 -C 6 -cycloalkyloxy-,
 (3- to 10-membered heterocycloalkyl)-, 
 (3- to 10-membered heterocycloalkyl)-O—, C 5 -C 8 -cycloalkenyloxy-, 
 (5- to 10-membered heterocycloalkenyl)-, 
 (5- to 10-membered heterocycloalkenyl)-O—, —NR 5a R 5b , —SCF 3  or —SF 5  group; 
 wherein said C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, C 1 -C 6 -alkoxy-, C 3 -C 6 -cycloalkyl-, C 4 -C 8 -cycloalkenyl-, C 3 -C 6 -cycloalkyloxy-, 
 (3- to 10-membered heterocycloalkyl)-, 
 (3- to 10-membered heterocycloalkyl)-O—, C 5 -C 8 -cycloalkenyloxy-, 
 (5- to 10-membered heterocycloalkenyl)-, 
 (5- to 10-membered heterocycloalkenyl)-O— group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 4  groups; 
 
         R 2  represents a hydrogen atom, a halogen atom or a group selected from: C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, C 4 -C 6 -cycloalkenyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 10-membered heterocycloalkyl-,
 4- to 10-membered heterocycloalkenyl-, aryl-, heteroaryl-, cyano-, —(CH 2 ) q —X—(CH 2 ) p —R 3 ; 
 wherein said C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, C 4 -C 6 -cycloalkenyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, 3- to 10-membered heterocycloalkyl-, 
 4- to 10-membered heterocycloalkenyl-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 4  groups; 
 
         X represents a bond or a bivalent group selected from: —O—, —S—, —S(═O)—, —S(═O) 2 —, —S(═O)—(NR 3a )—, —(NR 3a )—S(═O)—, —S(═O) 2 —(NR 3a )—, —(NR 3a )—S(═O) 2 —, —C(═O)—, —(NR 3a )—, —C(═O)—O—, —O—C(═O)—, —C(═S)—O—, —O—C(═S)—, —C(═O)—(NR 3a )—, —(NR 3a )—C(═O)—, —(NR 3a )—C(═O)—(NR 3b )—, —O—C(═O)—(NR 3a )—, —(NR 3a )—C(═O)—O—; 
         R 3a , R 3b  are the same or different and are independently selected from R 3 ; 
         R 3  represents a hydrogen atom or a group selected from C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-, heteroaryl-;
 wherein said C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 
 3- to 10-membered heterocycloalkyl-, aryl- or heteroaryl-group is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 4  groups; 
 
         or 
         R 3  together with R 3a  or R 3b  represent a 3- to 10-membered heterocycloalkyl- or a 4- to 10-membered heterocycloalkenyl-group, which is optionally substituted, identically or differently, with 1, 2, 3, 4 or 5 R 4  groups; 
         R 4  represents halo-, hydroxy-, oxo-(O═), cyano-, nitro-, C 1 -C 6 -alkyl-, C 2 -C 6 -alkenyl-, C 2 -C 6 -alkynyl-, halo-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, hydroxy-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, R 5 —O—, —C(═O)—R 5 , —C(═O)—O—R 5 , —O—C(═O)—R 5 , —N(R 5a )—C(═O)—R 5b , —N(R 5a )—C(═O)—NR 5b R 5c , —NR 5a R 5b , —C(═O)—NR 5a R 5b , R 5 —S—, R 5 —S(═O)—, R 5 —S(═O) 2 —, —N(R 5a )—S(═O)—R 5b , —S(═O)—NR 5a R 5b , —N(R 5a )—S(═O) 2 —R 5b , —S(═O) 2 —NR 5a R 5b , —S(═O)(═NR 5a )R 5b , —S(═O)(═NR 5a )R 5b  or —N═S(═O)(R 5a )R 5b ; 
         R 5a , R 5b , R 5C  are the same or different and are independently selected from R 5 ; 
         R 5  represents a hydrogen atom, a C 1 -C 6 -alkyl- or a C 3 -C 6 -cycloalkyl-group; 
         or 
         R 5a  and R 5b , 
         or R 5a  and R 5c , 
         or R 5b  and R 5c  together may form a C 2 -C 6 -alkylene group, in which optionally one methylene can be replaced by —O—, —C(═O)—, —NH—, or —N(C 1 -C 4 -alkyl)-; 
         p represents an integer of 0, 1, 2 or 3; 
         q represents an integer of 0, 1, 2 or 3; 
         or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 
       
     
     
       2. A compound according to  claim 1 , wherein:
 A represents: 
 
       
         
           
           
               
               
           
         
         
           wherein * indicates the point of attachment of said groups with the rest of the molecule. 
         
       
     
     
       3. A compound according to  claim 1 , wherein:
 A represents: 
 
       
         
           
           
               
               
           
         
         
           wherein * indicates the point of attachment of said groups with the rest of the molecule. 
         
       
     
     
       4. A compound according to  claim 1 , wherein:
 R 1a  represents a hydrogen atom or a group selected from:
 C 1 -C 3 -alkyl-, C 1 -C 3 -alkoxy-, halo-; 
 
 R 1b , R 1c , R 1d  represents a hydrogen atom. 
 
     
     
       5. A compound according to  claim 1 , wherein:
 R 1a  does not represent a hydrogen atom. 
 
     
     
       6. A compound according to  claim 1 , wherein:
 R 2  represents a hydrogen atom, a halogen atom, or a group selected from: C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, aryl-, cyano-, (CH 2 ) q —X—(CH 2 ) p —R 3 ; 
 wherein said C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl- or aryl-group is optionally substituted, identically or differently, with 1, 2 or 3 R 4  groups; 
 X represents a bond or a bivalent group selected from:
 —O—, —C(═O)—, —C(═O)—(NR 3a )—, —(NR 3a )—C(═O)—; 
 
 R 3a  represents a hydrogen atom or a group selected from C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl-, aryl-;
 wherein said C 1 -C 6 -alkyl-, C 3 -C 6 -cycloalkyl-, 3- to 10-membered heterocycloalkyl- or aryl-group is optionally substituted, identically or differently, with 1, 2 or 3 R 4  groups; 
 
 R 4  represents halo-, hydroxy-, oxo-(0=), cyano-, nitro-, C 1 -C 6 -alkyl-, halo-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-, halo-C 1 -C 6 -alkoxy-, hydroxy-C 1 -C 6 -alkyl-, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl-, R 5 —O—, —C(═O)—R 5 , —C(═O)—O—R 5 , —O—C(═O)—R 5 , —C(═O)—NR 5a R 5b . 
 
     
     
       7. A compound according to  claim 1 , which is selected from the group consisting of:
 6-{[2-(Cyclopropylmethyl)[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}-1,3-benzothiazol-2(3H)-one, 
 6-[(2-Cyclobutyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl)amino]-1,3-benzothiazol-2(3H)-one, 
 6-[(2-Cyclohexyl[1,3]thiazolo[5,4-d]pyrimidin-7-yl)amino]-1,3-benzothiazol-2(3H)-one, 
 2-Benzyl-N-(6-methoxy-1H-indazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine, 
 N-(6-Methoxy-1H-indazol-5-yl)-2-(methoxymethyl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine, 
 6-[(2-Cyclobutyl [1,3]thiazolo[5,4-d]pyrimidin-7-yl)amino]-5-methoxy-1,3-benzothiazol-2(3H)-one, 
 6-[(2-Cyclohexyl [1,3]thiazolo[5,4-d]pyrimidin-7-yl)amino]-5-methoxy-1,3-benzothiazol-2(3H)-one, 
 2-Cyclohexyl-N-(1H-indazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine, 
 2-(Cyclopropylmethyl)-N-(1H-indazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine, 
 2-Cyclobutyl-N-(1H-indazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine, 
 2-Benzyl-N-(1H-indazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine, 
 1-(3-Hydroxy-3-methylazetidin-1-yl)-4-[7-(1H-indazol-5-ylamino)[1,3]thiazolo[5,4-d]pyrimidin-2-yl]butan-1-one, 
 4-[7-(1H-Indazol-5-ylamino)[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-N,N-dimethylbutanamide, 
 1-(3-Hydroxy-3-methylazetidin-1-yl)-3-[7-(1H-indazol-5-ylamino)[1,3]thiazolo[5,4-d]pyrimidin-2-yl]propan-1-one, 
 N-(6-Methoxy-1H-indazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine, 
 N-(1H-Indazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine, 
 2-(2-Phenylethyl)-N-[6-(propan-2-yloxy)-1H-indazol-5-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine, 
 5-Methoxy-6-([1,3]thiazolo[5,4-d]pyrimidin-7-ylamino)-1,3-benzothiazol-2(3H)-one, 
 6-([1,3]Thiazolo[5,4-d]pyrimidin-7-ylamino)-1,3-benzothiazol-2(3H)-one, 
 2-[(Benzyloxy)methyl]-N-(6-methoxy-1H-indazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine, 
 3-[7-(1H-Indazol-5-ylamino)[1,3]thiazolo[5,4-d]pyrimidin-2-yl]-N,N-dimethylpropanamide, 
 N-(6-Methoxy-1H-indazol-5-yl)-2-(2-phenylethyl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine, 
 N-(1H-Indazol-5-yl)-2-(2-phenylethyl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine, 
 6-{[2-(2-Phenylethyl)[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}-1,3-benzothiazol-2(3H)-one, 
 5-Methoxy-6-{[2-(2-phenylethyl)[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}-1,3-benzothiazol-2(3H)-one, 
 4-{7-[(6-Methoxy-1H-indazol-5-yl)amino][ 1,3]thiazolo[5,4-d]pyrimidin-2-yl}-N,N-dimethylbutanamide, 
 N,N-Dimethyl-7-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino][1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 7-[(5-Methoxy-2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]-N,N-dimethyl [1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 7-[(6-Methoxy-1H-indazol-5-yl)amino]-N,N-dimethyl [1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 7-[(6-Ethoxy-1H-indazol-5-yl)amino]-N,N-dimethyl [1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 [7-(1H-Indazol-5-ylamino)[1,3]thiazolo[5,4-d]pyrimidin-2-yl]piperidin-1-yl)methanone, 
 6-{[2-(Piperidin-1-ylcarbonyl)[1,3]thiazolo[5,4-d]pyrimidin-7-yl]amino}-1,3-benzothiazol-2(3H)-one, 
 {7-[(6-Methoxy-1H-indazol-5-yl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}(piperidin-1-yl)methanone, 
 {7-[(6-Ethoxy-1H-indazol-5-yl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}(piperidin-1-yl)methanone, Piperidin-1-yl(7-{[6-(propan-2-yloxy)-1H-indazol-5-yl]amino}[1,3]thiazolo[5,4-d]pyrimidin-2-yl)methanone, 
 N-[2-(Dimethylamino)-2-oxoethyl]-7-(1H-indazol-5-ylamino)-N-methyl [1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 N-[2-(Dimethylamino)-2-oxoethyl]-N-methyl-7-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino][1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 N-[2-(Dimethylamino)-2-oxoethyl]-7-[(6-methoxy-1H-indazol-5-yl)amino]-N-methyl [1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 N-[2-(Dimethylamino)-2-oxoethyl]-N-methyl-7-{[6-(propan-2-yloxy)-1H-indazol-5-yl]amino}[1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 N-[3-(Dimethylamino)-3-oxopropyl]-7-(1H-indazol-5-ylamino)-N-methyl[1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 N-[3-(Dimethylamino)-3-oxopropyl]-N-methyl-7-[(2-oxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino][1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 N-[3-(Dimethylamino)-3-oxopropyl]-7-[(6-ethoxy-1H-indazol-5-yl)amino]-N-methyl[1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 7-(1H-Indazol-5-ylamino)-N,N-dimethyl[1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 N,N-Dimethyl-7-{[6-(propan-2-yloxy)-1H-indazol-5-yl]amino}[1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 N-[2-(Dimethylamino)-2-oxoethyl]-7-[(6-ethoxy-1H-indazol-5-yl)amino]-N-methyl[1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 N-[3-(Dimethylamino)-3-oxopropyl]-7-[(6-methoxy-1H-indazol-5-yl)amino]-N-methyl[1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 N-[3-(Dimethylamino)-3-oxopropyl]-7-[(6-isopropoxy-1H-indazol-5-yl)amino]-N-methyl[1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same. 
 
     
     
       8. A method of preparing a compound of general formula I according to  claim 1 , comprising reacting an intermediate compound of general formula III: 
       
         
           
           
               
               
           
         
         in which R 2  is as defined in  claim 1  and LG represents a leaving group; 
         with an intermediate compound of general formula II-A or II-B: 
       
       
         
           
           
               
               
           
         
         in which R 1a , R 1b , R 1c  and R 1d  are as defined in  claim 1  and PG represents a protective group or a hydrogen atom; 
         thus providing a compound of general formula I′-A, I′-B or I: 
       
       
         
           
           
               
               
           
         
         in which R 1a , R 1b , R 1c , R 1d , R 2 , and A are as defined in  claim 1 , PG represents a protective group or a hydrogen atom. 
       
     
     
       9. A compound selected from:
 7-Chloro-2-(cyclopropylmethyl)[1,3]thiazolo[5,4-d]pyrimidine, 
 7-Chloro-2-cyclohexyl[1,3]thiazolo[5,4-d]pyrimidine, 
 7-Chloro-2-(methoxymethyl)[1,3]thiazolo[5,4-d]pyrimidine, 
 7-chloro-2-cyclobutyl[1,3]thiazolo[5,4-d]pyrimidine, 
 ethyl 4-(7-chloro[1,3]thiazolo[5,4-d]pyrimidin-2-yl)butanoate, 
 ethyl 3-(7-chloro[1,3]thiazolo[5,4-d]pyrimidin-2-yl)propanoate, 
 7-chloro-2-(2-phenylethyl)[1,3]thiazolo[5,4-d]pyrimidine, 
 2-[(benzyloxy)methyl]-7-chloro[1,3]thiazolo[5,4-d]pyrimidine, 
 N,N-dimethyl-7-(methylsulfonyl)[1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 [7-(methylsulfonyl)[1,3]thiazolo[5,4-d]pyrimidin-2-yl]piperidin-1-yl)methanone, 
 N-[2-(dimethylamino)-2-oxoethyl]-N-methyl-7-(methylsulfonyl)[1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide, 
 N-[3-(dimethylamino)-3-oxopropyl]-N-methyl-7-(methylsulfonyl)[1,3]thiazolo[5,4-d]pyrimidine-2-carboxamide. 
 
     
     
       10. A method of inhibiting the MKNK-1 pathway comprising administering a therapeutically effective compound according to  claim 1  to a patient in need thereof. 
     
     
       11. A method of treating a haematological tumour, solid tumour or metastases thereof selected from leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours, brain tumours and brain metastases, tumours of the thorax, non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours, renal, bladder and prostate tumours, skin tumours, and sarcomas, and metastases thereof comprising administering to a patient in need thereof a therapeutic amount of a compound of  claim 1 .